Intraperitoneal (IP) administration of anti-cancer drugs is a theoretically compelling therapeutic option for epithelial ovarian cancer. However, translation of the theoretical advantage to clinical benefits is hampered by difficulties in IP chemotherapy due to several reasons including short residence time of drugs in the peritoneum, potential of pan-peritoneal toxicity, and insufficient intracellular uptake/accumulation of the anti-cancer drugs. We propose to develop a new form of polymeric nanoparticles (NPs) that will overcome these problems. The LONG TERM GOAL of our research is to develop a tumor-specific nanocarrier of anti-cancer drugs for safe and efficient IP chemotherapy of ovarian cancer. The OBJECTIVE of this study is to create poly(lactic-co- glycolic acid) (PLGA) NPs as a carrier of paclitaxel, which are inert in normal tissues but transform to a reactive form in the peritumoral region (Peritumorally Transformable NPs or PTNPs). This will allow the NPs to have a minimal interaction with non-cancerous tissues, yet be readily taken up and accumulate in ovarian tumor cells providing an intracellular drug reservoir. To this end, we will engineer a surface layer on the PLGA NP drug carrier core, consisting of (a) a conjugate of polyethylene glycol (PEG) and matrix metalloproteinase (MMP) specific substrate peptide (MMP substrate), and (b) a fragment of trans- activating transcriptional activator (TAT) protein (TAT peptide, TATp). The function of each component is that (i) PEG will shield the TATp and NPs when present, preventing interactions between PTNPs and non- cancerous tissues en route to the tumors;(ii) MMP substrate will allow the PEG to cleave off when the PTNPs are exposed to MMPs (MMP-2, MMP-9), which are overexpressed in the epithelial ovarian tumors;and (iii) then exposed TATp will promote cellular uptake and retention of the PTNPs in the tumor cells. The underlying HYPOTHESES are that (i) MMPs that are more specifically concentrated in the peritumoral region can be utilized to cleave MMP substrate and transform polymeric NPs from a PEGylated form to one coated with TATp, and (ii) this transformation will enable the NPs to interact with tumor cells in a tumor-specific manner. To prove this hypothesis, we will create PTNPs by preparing NPs with TATp-PLGA conjugate and PEG-MMP substrate-PLGA conjugate or preparing NPs with TATp-PLGA conjugate first and then conjugating PEG-MMP substrate (Aim 1). Simultaneously, in Aim 2, we will determine in-vivo MMP levels in normal tissues, ascites, and tumor tissues in an orthotopic xenograft model of human ovarian cancer. This information will be used in evaluating the new NPs in vitro with respect to cellular uptake, intracellular trafficking, and the efficacy of paclitaxel delivered by the PTNPs. The novel PTNPs should provide tumor-specific intracellular drug delivery, which would reduce the total dose requirement, improve the anti-tumor efficacy, and maximize the pharmacokinetic advantage of IP chemotherapy of ovarian cancers. The proposed study will be a significant step toward more effective and safe management of advanced ovarian cancers. PUBLIC HEALTH RELEVANCE: We propose to develop a tumor-specific nanocarrier of anti-cancer drugs for safe and efficient intraperitoneal (IP) chemotherapy of ovarian cancer. IP chemotherapy is a theoretically compelling therapeutic option for epithelial ovarian cancer, but translation of this theoretical advantage to clinical benefits is hampered by difficulties in IP drug delivery. We aim to overcome these challenges by engineering a novel nanocarrier that will have a minimal interaction with non-cancerous tissues, yet be readily taken up and accumulate in the tumor cells providing an intracellular drug reservoir, through peritumoral surface transformation.